Laparoscopic Heller myotomy versus peroral endoscopic myotomy in children with esophageal achalasia: a systematic review and meta-analysis

Introduction

Esophageal achalasia (EA) is a rare disorder of the lower esophageal sphincter (LES) that leads to dysfunctional motility of the esophagus [1]. It is extremely rare in childhood, with an incidence of only 0.11/100,000 children annually [1]. The clinical presentation includes dysphagia to fluids and solids, vomiting, chest pain, regurgitation, recurrent episodes of chest infections due to aspiration, and weight loss [1]. Although in most cases is idiopathic, in some instances it may be associated with Trisomy 21, AAA syndrome (achalasia, alacrima, and adrenocorticotropic hormone insufficiency), Chagas disease, congenital hypoventilation syndrome, glucocorticoid insufficiency, eosinophilic esophagitis, or familial dysautonomia [1].

The precise etiology of EA is still unclear, but it may be associated with autoimmunity, viral infection or neurodegeneration and other factors [1]. Combined diagnostic investigations are used to confirm the diagnosis of EA. A barium meal is used to rule out esophageal strictures and shows the delay in transition through the LES (bird-beak appearance) [2]. Esophagoscopy is used to preclude pseudo-achalasia, assess the esophageal wall and rule out esophagitis, Trypanosoma cruzi, malignancy, reflux esophagitis, and other causes of impaired esophageal motility [1]. However, high-resolution manometry or high-resolution impedance manometry (HRIM) is considered the gold standard method to demonstrate EA, by demonstrating patterns of esophageal contractility [2].

Although there are multiple modalities for the treatment of EA, surgery remains the most successful treatment of choice [1]. Currently, laparoscopic Heller myotomy (LHM) has become the gold standard in the treatment of EA [1]. However, more recently, a more attractive procedure, peroral esophageal myotomy (POEM) [3], has been proposed for the management of EA. POEM has been used in adults with excellent results [3], and has started to be adopted by pediatric surgeons and gastroenterologists [4]. As there is no curative treatment or any globalized consensus on 1 gold-standard intervention, the present study aimed to provide a systematic review and meta-analysis, comparing the reported results concerning the efficacy and outcomes of LHM and POEM for the treatment of EA in children.

Materials and methods

This meta-analysis adhered to the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) statement (Appendix A) [5]. The protocol was registered with the International Prospective Register of Ongoing Systematic Reviews (PROSPERO), with registration number CRD42023389402.

Results

Literature search and included studies

A total of 32 articles published between January 1999 and June 2023 were retrieved via the database search and were included in this meta-analysis [1,4,13-42] (Fig. 1).

Figure 1 Flow chart showing the design of the systematic review

Study characteristics and demographics

A summary of the characteristics of the eligible studies assessing the efficacy and outcome of LHM and POEM for EA is presented in Table 1. The total patient population included 800 children (female: 345, male/female: 1:0.73), aged 1-17 years. LHM was performed in 293 patients, and POEM in 507. The mean or median ages of patients participating in each eligible study are shown in Table 1. The majority of the studies were retrospective; there were only 2 prospective studies. Only 3 studies were comparative, as they compared 2 different intervention methods (myotomy, dilation, POEM), whereas the rest simply reported the results of a single method. For the comparative studies, we extracted the results of the different interventions and treated them as 2 separate studies. The evaluation of the intervention was conducted using the differences in the mean ES and the LES between pre- and post-operation. The ES is a simple symptom score (dysphagia, regurgitation, chest pain and weight loss), which was designed to quantify the response of symptoms to treatment [43]. The lower the mean ES and the lower the mean LES the better the results of the intervention.

Table 1 Summary of characteristics of the included studies

Evaluation of ES in POEM

A total of 11 studies reported the mean ES difference pre- and postoperatively for the POEM procedure (Fig. 2, Supplementary Table 1). All studies demonstrated a higher mean preoperative ES compared to the postoperative value. According to the random-effects model, the summary preoperative to postoperative difference in mean ES for the POEM procedure was 4.387 (95% confidence interval [CI] 3.799-4.974), which was statistically significantly different to zero (z=14.64, P<0.001) (Fig. 2). According to the chi-square test for heterogeneity there was statistically significant heterogeneity (I²=74%, chi-square=38.51, degrees of freedom (d.f.)=10, P<0.001) (Supplementary Table 1).

Figure 2 Forrest plot of mean Eckardt score difference, preoperatively and postoperatively, for the peroral endoscopic myotomy (POEM) procedure

SMD, standardized mean difference; CI, confidence interval

Evaluation of LES pressure in POEM

A total of 8 studies reported the mean LES pressure difference pre- and postoperatively for the POEM procedure (Fig. 3, Supplementary Table 2). All the studies demonstrated a higher preoperative mean LES pressure compared to the mean postoperative value. According to the result of the random-effects model the summary preoperative to postoperative difference in mean LES for the POEM procedure was 3.63 mmHg (95%CI 2.247-3.879), which was statistically significantly different to zero (z=7.36, P<0.001) (Fig. 3). According to the chi-square test for heterogeneity there was statistically significant heterogeneity (I²=78.4%, chi-square=31.47, d.f.=7, P<0.001) (Supplementary Table 2).

Figure 3 Forrest plot of mean lower esophageal sphincter (LES) pressure difference preoperatively and postoperatively for the peroral endoscopic myotomy (POEM) procedure

SMD, standardized mean difference; CI, confidence interval

Evaluation of operation duration in LHM and POEM

A total of 7 studies reported the mean value and the standard deviation, and 3 more the median value and the range, of the operation duration. The pooled estimate of operation duration was 97.5 min (95%CI 79.2-115.7) (Fig. 4). Heterogeneity was very high (I²=95%, τ²=787.5). Significant heterogeneity was found among methods of operation (Q test P=0.014). The pooled estimate of operation duration was 130.2 min (95%CI 95.8-164.5) for the LHM method, compared with 82.5 min (95%CI 66.4, 98.6) for POEM (Supplementary Table 3).

Figure 4 Forest plot of random-effects meta-analysis of the operation time (min) over all studies and by method of operation: laparoscopic Heller myotomy (LHM) vs. peroral endoscopic myotomy (POEM)

ES, Eckardt score; CI, confidence interval

Evaluation of length of hospital stay in LHM and POEM

The mean value and standard deviation for the length of hospital stay were reported in 10 studies, while the median and range were reported in 4 more studies. The pooled estimate of length of stay was 3.3 days (95%CI 2.6-3.9) (Fig. 5). Again, heterogeneity among studies was very high (I²=97%, τ²=1.15). There was no significant heterogeneity between methods in length of stay (Q test P=0.201). The pooled estimate of hospital stay was 2.8 days (95%CI 2.16-3.37) for the LHM method, compared with 3.6 days (95%CI 2.48-4.70) for POEM (Supplementary Table 4).

Figure 5 Forest plot of random-effects meta-analysis of the length of hospital stay (days) over all studies and by method of operation: laparoscopic Heller myotomy (LHM) vs. peroral endoscopic myotomy (POEM)

ES, Eckardt score; CI, confidence interval

Discussion

EA is a rare disorder in children and there are limited data regarding the effectiveness of current treatment methods. To our knowledge, this is the first systematic review with meta-analysis to evaluate the efficacy of the 2 most popular treatment modalities, POEM and LHM, in children, assessing the outcome in terms of the differences in mean ES and LES pressure from pre- to post-operation, in combination with perioperative characteristics such as operation duration and length of hospital stay. We chose to use these 2 parameters, as both ES and LES pressure have been proposed as objective tools for measuring the response to therapy [43].

Our results revealed that POEM, an established interventional method of treatment for EA in adults, is effective in children with EA, as all studies demonstrated a lower value of mean ES postoperatively compared to the mean value preoperatively, while the pooled mean reduction in ES was statistically significant. This indicates that the POEM procedure leads to the resolution of symptoms, improving the quality of life of pediatric patients. At the same time, this meta-analysis revealed that the duration of the POEM procedure is significantly shorter compared to LHM, whereas the length of hospitalization is similar for the 2 methods.

However, a comparison of the 2 treatment methods regarding the measurement of outcome using ES and LES was not possible, as the review of the current literature yielded very few studies that reported results of ES and LES pressure when LHM was performed. More specifically, only Waldhausen et al measured LES pressure pre- and postoperatively, reporting that it decreased significantly from >40 mmHg preoperatively to <6-10 mmHg after the procedure [13]. Notably, no study reported ES. This finding could potentially be attributed to the fact that ES is a scoring system initially developed for assessing the severity of symptoms in adults. The symptoms might differ in younger children, while their evaluation is probably more difficult in this age group. Future discussions could focus on the need for adapting or creating a separate ES for the pediatric population. As a result, we were not able to evaluate the reduction in mean ES and LES pressure postoperatively.

In contrast, other results of the current evaluation of these 2 methods for the management of pediatric EA, concerning the duration of the procedure and the length of hospitalization, were interesting. According to our meta-analysis, the LHM procedure takes longer (approximately 50 min more) than POEM, as POEM is a less invasive method compared to LHM. The operative duration of both methods was probably shorter when they were performed by experienced hands. EA remains an extremely rare condition in children. In particular, POEM is a complex procedure, and is perhaps more difficult in a pediatric population with potentially high-risk complications, such as perforation and mediastinitis. Consequently, it should only be performed in children by experienced endoscopists with a knowledge of pediatric anatomy, advanced skills, and the ability to manage complications. As there is high heterogeneity regarding the management of pediatric achalasia among different centers worldwide, both procedures should be performed in high-volume experienced centers, in order to reduce complications and improve short- and long-term outcomes. Finally, the development of evidence-based global clinical guidelines is essential [3].

No significant difference in length of hospital stay was observed, as the pooled mean hospital stay of patients was approximately 3-4 days in both techniques. In contrast to our results, studies that have been carried out in adults demonstrate that POEM is associated with a shorter length of hospital stay compared to LHM [44]. This finding could potentially be attributed to the specific features of the pediatric population, to parental stress, and to surgeons and gastroenterologists choosing to continue hospitalization in order to monitor for postoperative complications, recurrent symptoms and adequate nutrition and physical growth, contributing to an increase in healthcare costs.

So far, because of the low incidence of achalasia in the pediatric population, there are limited data available on the efficacy of POEM in children. The first systematic review and meta-analysis addressing the effectiveness of this promising treatment modality for pediatric achalasia was conducted by Lee et al, who demonstrated that POEM was efficacious and safe for treating achalasia in children, with a significant mean decrease in both ES and LES pressure after the procedure, by 6.88 points and 20.73 mmHg, respectively [45]. However, their findings were limited by the small total number of patients (n=142), and by the inclusion of non-randomized trials and low-quality studies. Recently, Zhong et al performed a systematic review and meta-analysis in order to evaluate the utility of this novel endoscopic technique in pediatric patients [46]. They reported that clinical success was achieved in the majority of children, with a significant mean reduction in ES and LES pressure following POEM, by 6.76 points and 19.38 mmHg, respectively [46]. However, this review included only observational studies and POEM was not compared with alternative therapeutic methods. Nabi et al carried out the most recent systematic review and meta-analysis that aimed to explore the clinical outcomes of POEM for pediatric achalasia [47]. Similarly, this study supported the claim that POEM is an effective intervention in children with achalasia, while the pooled mean reduction in ES was 6.71 post-POEM [47]. Overall, the results of these meta-analyses are consistent with our findings, demonstrating the efficacy of this minimally invasive procedure that could provide long-term symptom resolution in young patients.

Given that the published comparative data are insufficient to determine the ideal management of pediatric achalasia, our current knowledge of treatment algorithms is largely based on the adult literature. Although a treatment strategy for achalasia in pediatric patients remains a challenge, experience from adult studies can help and guide clinicians in treatment selection, according to relevant clinical factors. In general, based on network meta-analyses in adults, POEM and LHM have comparable efficacy and similar clinical success for the management of achalasia [48-50]. In 2 recent systematic reviews and meta-analyses, both POEM and LHM had greater efficacy than pneumatic dilation, but neither was significantly superior to the other [49,50]. In the same context, Shiu et al reported that POEM demonstrated similar results to LHM, and suggested that POEM with an anterior or posterior approach, and LHM with Dor or Toupet fundoplication, are the best initial treatments for achalasia [48].

A strength of our study is the systematic, comprehensive and detailed approach to evaluating POEM and LHM outcomes, based on ES and LES pressure pre- and postoperatively, as well as perioperative characteristics such as operative duration and length of hospitalization, all in accordance with the PRISMA reporting guidelines and following a predefined registered protocol. Moreover, the majority of the eligible studies had a low overall risk of bias and applicability concerns. Nevertheless, there are also study limitations to consider. First, the quality of meta-analyses will always be determined by the quality of the individual studies included in the analysis. The majority of the individual included studies were retrospective, while only 3 were prospective. As result, there is a lack of high-quality data available in the literature and there are no randomized controlled trials. Moreover, there are limited data for LHM, making it impossible to compare the 2 methods. The high heterogeneity regarding ES and LES pressure between the studies was probably associated with the varying design of the studies, the internal protocols, and the postoperative follow up of each institution.

In the present study, a comparison of the 2 most popular and effective methods for EA treatment in children, regarding their impact on ES and LES, was not possible, because of the inappropriate design of previous studies focusing on the LHM procedure. Therefore, our meta-analysis was restricted to the POEM method, which showed positive outcomes regarding ES and LES pressure pre- and postoperatively. On the other hand, this study demonstrates that POEM’s mean procedure duration is shorter than that of LHM, while the length of hospital stay is similar. We highlight the need for carrying out well-designed studies with homogeneous use of objective diagnostic tools and long-term follow up of pediatric patients with EA, so as to further clarify the differences between the 2 methods.